Whole-cell voltage-clamp and single channel recording techniques were used to study drug interactions with N-methyl-D-aspartate (NMDA) and non- NMDA receptor coupled cation and gamma-aminobutyric acid(A) (GABA(A) receptor-coupled Cl channels in cultured hippocampal neurons. The aim of this work was to explore new strategies for the rational development of antiepileptic drugs based upon their interaction with neuronal ion channel systems. Work was focused in the following areas: (i) pharmacology of Ca2+-permeable, inwardly rectifying AMPA receptors, (ii) mechanism of inward rectification of Ca2+-permeable AMPA receptors; (iii) mechanism of action of felbamate and the related dicarbamate meprobamate, (iv) effects of the polyamine toxins argiotoxin 636 (ARG 636) and philanthotoxin 434 (PHTX 434) on NMDA receptors; and (v) studies on the interaction of the anticonvulsant remacemide and its des-glycine metabolite with NMDA receptors. AMPA receptors lacking the GluR2 subunit have an inwardly rectifying current-voltage relationship and are permeable to Ca2+; a subpopulation of cultured hippocampal neurons selectively express these receptors. The polyamine toxins PHTX 343 and ARG 636 were found to selectively block Ca2+-permeable AMPA receptors in these neurons, but to have minimal effects on neurons expressing Ca2+- impermeable AMPA receptors. Support was obtained for the hypothesis that inward rectification of Ca2+-permeable AMPA receptors occurs as a result of voltage-dependent channel block by internal polyamines. Felbamate, a newly approved antiepileptic agent, and the related dicarbamate meprobamate were found to inhibit NMDA receptors by a channel blocking action and also possibly by distinct effects on channel gating. It has been suggested that the NMDA receptor blocking activity of felbamate may result from competitive antagonism at the glycine recognition site of the NMDA receptor. Several observations failed to support such a glycine site interaction. PHTX 343 and ARG 636 were found to inhibit NMDA receptors via open channel block and competitive antagonism at the NMDA recognition site. In addition, ARG 636 exerted a polyamine-like facilitation of NMDA receptor currents. The interaction of the novel anticonvulsant remacemide and its des-glycine metabolite with NMDA receptors was examined in whole cell voltage-clamp recordings from cultured rat hippocampal neurons and in binding studies with [3H]dizocilpine in rat forebrain membranes. The metabolite was found to be a potent, stereoselective open channel blocker whereas remacemide itself was a weak NMDA receptor antagonist which acted as an allosteric antagonist and also, like the metabolite, as a channel blocker. Overall, the functional NMDA receptor blocking activity of remacemide in vivo is likely to be mediated predominantly by the des- glycine metabolite.